Vemurafenib BRAF (gene)

figure 4: structures of vemurafenib (right) , precursor, plx 4720 (left), 2 inhibitors of active conformation of b-raf kinase domain

plx4032 (vemurafenib) v600 mutant b-raf inhibitor approved fda treatment of late-stage melanoma. unlike bay43-9006, inhibits inactive form of kinase domain, vemurafenib inhibits active dfg-in form of kinase, firmly anchoring in atp-binding site. inhibiting active form of kinase, vemurafenib selectively inhibits proliferation of cells unregulated b-raf, cause cancer.

since vemurafenib differs precursor, plx4720, in phenyl ring added pharmacokinetic reasons, plx4720 s mode of action equivalent vemurafenib s. plx4720 has affinity atp binding site partially because anchor region, 7-azaindole bicyclic, differs natural adenine occupies site in 2 places nitrogen atoms have been replaced carbon. enables strong intermolecular interactions n7 hydrogen bonding c532 , n1 hydrogen bonding q530 preserved. excellent fit within atp-binding hydrophobic pocket (c532, w531, t529, l514, a481) increases binding affinity well. ketone linker hydrogen bonding water , difluoro-phenyl fit in second hydrophobic pocket (a481, v482, k483, v471, i527, t529, l514, , f583) contribute exceptionally high binding affinity overall. selective binding active raf accomplished terminal propyl group binds raf-selective pocket created shift of αc helix. selectivity active conformation of kinase further increased ph-sensitive deprotonated sulfonamide group stabilized hydrogen bonding backbone peptide nh of d594 in active state. in inactive state, inhibitor s sulfonamide group interacts backbone carbonyl of residue instead, creating repulsion. thus, vemurafenib binds preferentially active state of b-raf s kinase domain.